DESCRIPTION (Verbatim from Applicant's abstract): The relationship between renal blood flow and glomerular filtration rate is well established. A decrease in renal blood flow lowers glomerular filtration rate, triggering water retention and increases in extracellular fluid volume, cardiac output and arterial pressure. If both renal blood flow and glomerular filtration rate remain suppressed, the initial steps in the development of hypertension have taken place. Since changes in renal blood flow have been implicated in certain vascular disorders, including hypertension and renal vasospasm, this research will help fill the existing gap of knowledge regarding the relationship between ion channel regulation and vascular reactivity in the renal vasculature. It has been clearly shown that Kv, KCa and L-type Ca2+ channel activity in small resistance arterioles of the kidney are altered in the spontaneously hypertensive rat (SHR) and deoxycorticosterone acetate (DOCA) hypertensive rat when compared to their proper control. Yet the mechanism(s) by which these alterations take place has yet to be elucidate. The general hypothesis of this application is that regulation of K+ and Ca2+ channel activity, either by signaling molecules or by a change in number, depolarize membrane potential in renal resistance arteriolar vascular smooth muscle cells from hypertensive rats thereby increasing vascular smooth muscle tone. Using a multifaceted approach of vascular reactivity, patch clamp electrophysiology, molecular techniques (Western blot and RNase protection) and confocal microscopy, this research project will advance our understanding of the involvement of membrane conductances in the regulation of renal vascular excitation-contraction coupling and blood pressure in health and disease. The aims of the proposed research are fourfold: (1) To biophysically and pharmacologically characterize the mechanism(s) by which there is a decrease in Kv channel current density in renal resistance arteriolar vascular smooth muscle cells of hypertensive rat models. (2) To biophysically and pharmacologically characterize the mechanism(s) by which there is an increase in L-type Ca2+ channel current density in renal resistance arteriolar vascular smooth muscle cells from hypertensive rat models. (3) To characterize the relationship between Ca2+ release from the sarcoplasmic reticulum, PKC and the depressed activity of KCa channels in renal resistance arterioles and renal vascular smooth muscle cells from hypertensive rat models. (4) To examine if lowering blood pressure with antisense gene therapy targeting the rennin-angiotensin system can prevent/reverse the mechanism(s) that lead to alterations in Kv, KCa, and L-type Ca2+ channel activity. The results from these studies should significantly increase our knowledge of the mechanism(s) of hormonal modulation of vascular tone in a clinically relevant tissue, the renal vascular bed and its role in the development of hypertension.